Is this the herald of a new era for amyloidosis?

On August 10, 2018, the FDA approved Alnylam’s Onpattro (patisiran) for the treatment of ATTR-FAP (polyneuropathy associated with amyloid transthyretin amyloidosis)1, marking several firsts, including the first ever therapy to be approved for any form of amyloidosis in the United States, as well as the first siRNA-based therapy to be approved anywhere in the world. The approval came as no surprise to anyone following the amyloidosis market; patisiran demonstrated impressive clinical performance in its pivotal Phase III trials and had previously been granted fast track and breakthrough therapy designations by the FDA. In addition, the CHMP recently adopted a positive opinion recommending patisiran’s marketing authorization in Europe. All eyes are now on the Ionis/Akcea, who await the FDA’s decision, due by October 6, 2018, on their candidate Tegsedi (inotersen) that also targets ATTR-FAP and has already bagged a regulatory approval for the indication in Europe. The two drugs, based on the same mechanistic approach and targeting the same patient population, seem set for a fierce competition in the United States and Europe.

What is RNA-based gene silencing and how is it useful against ATTR amyloidosis? ATTR amyloidosis is a progressively debilitating disease caused by the deposition of amyloid fibrils of misfolded transthyretin (TTR) protein into various organs. ATTR amyloidosis can be hereditary (hATTR amyloidosis) or non-hereditary (wtATTR amyloidosis), and hATTR amyloidosis is further categorized into familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC), based on the organ/tissue that is predominantly affected (i.e. the peripheral nerves and the heart, respectively).

Patisiran is a double-stranded siRNA that silences the TTR gene, by targeting its 3’ UTR, based on Alnylam’s Systemic RNAi technology that encapsulates the siRNA in a lipid nanoparticle for direct delivery into the liver and consistent gene silencing, while inotersen is an antisense RNA against the TTR mRNA, based on Ionis’ antisense RNA platform.

Patisiran has a first-to-market advantage in the United States and boasts a better safety and efficacy profile, but will that give it a competitive edge over inotersen?

With the FDA approval, patisiran is set for an earlier launch in the United States compared to inotersen, and will likely reap the commercial benefits of being the first mover. But with a regulatory decision less than 2 months away, inotersen is not far behind its rival.

The pivotal Phase III trials of patisiran and inotersen (APOLLO and NEURO-TTR, respectively) showed that the former has a more desirable clinical profile. Patisiran not only showed a higher improvement in the primary end points of efficacy, i.e., neuropathy impairment score (mNIS+7) and quality of life (Norfolk-QOL-DN), it also demonstrated a more advantageous safety and tolerability. The adverse events associated with patisiran treatment were mostly mild/moderate and limited to infusion reactions and peripheral edema, whereas inotersen treatment led to serious renal events and thrombocytopenia in five patients. Moreover, the rates of mortality and treatment discontinuation were lower than placebo for patisiran but higher than placebo for inotersen.

When considering this clinical data, the amyloidosis experts interviewed by the Decision Resources Group contend that they see patisiran as the preferred therapy over inotersen, particularly because of a better safety and tolerability profile of the former. However, these KOLs also note that patient choice could be a major determining factor in the uptake of the two drugs. Despite patisiran’s clinical advantage, some patient may find its intravenous route of administration, which typically takes a few hours of infusion, less convenient than inotersen’s subcutaneous delivery. Experts also note that neither of the two drugs is expected to benefit all the patients receiving it, so some patients may switch to inotersen following treatment failure with patisiran or vice versa. Therefore, despite a clinical edge and first-to-market advantage for patisiran, inotersen is still expected to garner a notable share of this market.

How will Alnylam’s marketing strategy for patisiran affect Akcea/Ionis’s plans with inotersen? Alnylam announced its pricing strategy for patisiran—a list price of $450,000/year and a net price of $345,000/year, taking into account rebates for the payers. The company also announced having agreed in principle to the terms of value-based agreements (VBAs) with certain commercial insurers, including Harvard Pilgrim and other major insurers.2 These agreements will ensure that the company gets reimbursed in full only if there is an evaluable clinical improvement in the patients comparable to that demonstrated in clinical trials. The payer rebates and VBAs will surely allow a smoother patient access to patisiran, and, despite a premium pricing, will likely prevent Alnylam from facing any major reimbursement hurdles in the United States. While the precise details of these agreements are undisclosed, Alnylam may also exploit its first-to-market advantage by entering into exclusive agreements with major payers. In theory, such exclusive agreements could prioritize patisiran’s access over inotersen, by excludingthe latter  from the MCO formularies altogether, or allowing access to it only through a step-therapy protocol after patisiran.

Although Akcea/Ionis have yet not declared their commercialization plans for inotersen, Alnylam’s position of advantage and its marketing strategy with patisiran may encourage Akcea/Ionis to seek similar agreements with payers, such as VBAs for inotersen, and be transparent with payer rebates like Alnylam. Moreover, now that Alnylam has effectively set the price ceiling in this market, we expect that Akcea/Ionis will price inotersen comparably to patisiran, to avoid undue loss of market share to their competitor.

What does the FDA approval of patisiran means for ATTR amyloidosis? With the exception of tafamidis (Pfizer’s Vyndaqel), approved for ATTR-FAP in Europe in 2011, no other therapies have been approved for ATTR amyloidosis and treatment is based on off-label use of drugs (e.g. diflunisal, doxycycline/TUDCA) with limited evidence of clinical benefit. Hence, there is a high unmet need for a disease-modifying therapy in ATTR amyloidosis and patisiran’s approval is unarguably a revolutionary step in that direction. However, it is not quite the leap that some expected given that patisiran’s FDA label does not support its use in patients with FAC or those with wtATTR amyloidosis (the predominant morbidity of which is cardiomyopathy). This is not surprising given that the APOLLO trial included patients with FAP with asymptomatic cardiac amyloid involvement, and although patisiran showed some improvement in the cardiac parameters of these patients, Alnylam may have to conduct specific trials in the cardiomyopathy population to earn a broader label. For the same reasons, inotersen, if approved, is expected to carry a similarly narrow label that would exclude the FAC and wtATTR amyloidosis patients; moreover, the adverse effects of the drug related to thrombocytopenia make it an unlikely candidate for future development for cardiomyopathy.

This means that, despite two promising therapies launching in this space, the majority of the ATTR amyloidosis patients (i.e., those with ATTR-FAC and/or wtATTR) will continue to lack an approved treatment, at least until further clinical data is available. In this regard, a more near-term ray of hope for the ATTR-cardiomyopathy patients could be Pfizer’s tafamidis, which is being evaluated in a Phase III trial (ATTR-ACT) in patients with FAC and wtATTR amyloidosis. Indeed, Pfizer recently announced positive interim results from the study, which created huge excitement in the amyloidosis community and raised high hopes of an upcoming therapy.3 It is worth noting that tafamidis was rejected by the FDA for ATTR-FAP in 2012, following which Pfizer started its development for ATTR-associated cardiomyopathy.

Is combination therapy an answer for ATTR amyloidosis? Interviewed amyloidosis experts note that an ideal treatment of ATTR amyloidosis would be a combination of two different and effective approaches, such as TTR stabilization and TTR gene silencing. In this regard, a combination of tafamidis and patisiran may become a viable therapeutic strategy for ATTR amyloidosis in the future, provided clinical studies conducted with the combination demonstrate favorable safety and tolerability and a superior efficacy over the two drugs alone. Although neither Pfizer nor Alnylam or Ionis/Akcea have announced any plans for such a study, interviewed experts contend that it would be worthwhile effort in the direction of fulfilling a high unmet need in amyloidosis. Regardless of the clinical data, the reimbursement for a combination of two premium-priced, branded therapies is likely to be cost-prohibitive.

This is an exciting time in the amyloidosis arena, with two back-to-back marketing authorizations granted in the United States and Europe and two more expected in the near future. However, there is still a long way to go in the fight against amyloidosis, and patisiran’s FDA approval is a stepping stone in that endeavor.

  1. Alnylum Pharmaceuticals, press release, August 10, 2018
  2. Alnylum Pharmaceuticals, press release, August 10, 2018
  3. Pfizer, press release, March 29, 2018.


For our in-depth analysis of the amyloidosis market, including the sales and uptake forecast of emerging therapies in ATTR and AL amyloidosis, please see our comprehensive Amyloidosis market assessment and sales forecast.


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